Fear Stress Research Articles

Effects of acute citalopram on the expression of conditioned freezing in naive versus chronic citalopram-treated rats

An acute challenge with selective serotonin (5-HT) reuptake inhibitors (SSRIs) reduces the conditioned freezing in rats, a model of anxiety. The increase in the 5-HT levels in the nerve terminal induced by SSRIs is closely related to its pharmacological effects. Clinically, SSRIs exert an anxiolytic effect after chronic treatment. The effects of repeated treatment with citalopram on conditioned freezing in rats were examined in the present study. Acute citalopram (10 mg/kg) reduced freezing at a short post-training interval (1 day) significantly. While the effect of citalopram (10 mg/kg) on freezing was diminished by prolonging the interval between conditioning and the exposure to conditioned fear stress, repeated citalopram (10 mg/kg) injection twice daily for 7 days restored the inhibitory effect of acute challenge of citalopram (10 mg/kg) on freezing. By prolonging the period between conditioning and exposure to conditioned fear stress, this model may have a more precise predictive validity of anxiety disorder as an animal model.

Pharmacokinetic interaction between tandospirone and fluvoxamine in the rat contextual conditioned fear stress model and its functional consequence: Involvement of cytochrome P450 3A4

In a previous study it was demonstrated that the anxiolytic action of tandospirone, a 5-hydroxytryptamine (5-HT)(1A) receptor agonist, is facilitated by cytochrome P450 (CYP) 3A4 inhibitors, such as ketoconazole and cimetidine. It is also known that fluvoxamine, a selective serotonin re-uptake inhibitor (SSRI), inhibits CYP3A4. The purpose of the present study was to clarify the pharmacokinetic interaction between tandospirone and fluvoxamine and to evaluate their combined effect in the rat anxiety model. The anxiolytic action of co-administration of tandospirone and fluvoxamine was examined using the rat contextual conditioned fear stress model. After testing the conditioned fear, plasma concentrations of tandospirone and its major metabolite 1-(2-pyrimidyl) piperazine were determined. One day after fear conditioning, both tandospirone (60 mg/kg, p.o.) and fluvoxamine (60 mg/kg, p.o.) significantly inhibited conditioned freezing and their combination effect was additive. In addition, plasma concentration of tandospirone was increased by fluvoxamine. There is a CYP3A4-related drug-drug interaction between tandospirone and fluvoxamine. Therefore, fluvoxamine may facilitate the anxiolytic effect of tandospirone via CYP3A4 inhibition.

Changes in amygdala neural activity that occur with the extinction of context-dependent conditioned fear stress

The purpose of the present study was to characterize functional changes in the amygdala that accompany the extinction of context-dependent conditioned fear stress in a rat, an animal model of anxiety. Specifically, the effect of extinction of conditioned fear-induced cyclic AMP responsive element-binding protein (CREB) phosphorylation in the amygdala was investigated using immunohistochemistry. Experiments demonstrated that CREB phosphorylation in the basal nucleus of the amygdala decreased with the extinction of context-dependent conditioned fear-induced freezing behavior. These data suggest that the basal nucleus of the amygdala plays an essential role in the expression of context-dependent conditioned fear. Further, this is the first study to demonstrate that CREB phosphorylation in the basal nucleus of the amygdala changes in parallel with the extinction of context-dependent conditioned fear.

Psychological Stress-induced Changes in Sleep Patterns and Its Generation Mechanism

Recent findings have increasingly shown that sleep patterns are significantly influenced by psychological stress, such as social defeat, novelty stress, contextual fear stress, and psychological stress induced by the communication box. However, the exact association between psychological stress and sleep is still poorly understood. Therefore, in the present paper we will review related work based on our recent investigations. We have previously reported that total rapid eye movement (REM) sleep, but not non-rapid eye movement (NREM) sleep that is enhanced by psychological stress induced by the communication box in rats (Cui et al., 2007). In past decades strong evidence showed that neurotransmitters play a key role in the variations of the sleep patterns, such as acetylcholine, GABA and others. In addition to neurotransmitters, the hypothalamic-pituitary-adrenal (HPA) axis is another important factor which influences sleep patterns. Therefore, this review will focus on the involvement of the neurotransmitters and the HPA axis in the changes of sleep patterns in response to psychological stress.

Effect of co-administration of the selective 5-HT 1A receptor antagonist WAY 100,635 and selective 5-HT 1B/1D receptor antagonist GR 127,935 on anxiolytic effect of citalopram in conditioned fear stress in the rat

This study investigated the effect of co-administration of the selective 5-HT 1A receptor antagonist WAY 100,635 and selective 5-HT 1B/1D receptor antagonist GR 127,935 with a subactive dose of citalopram [selective serotonin (5-HT) reuptake inhibitor (SSRI)] on the expression of conditioned freezing, an index of fear. In the present study, acute administration of citalopram (s.c.) reduced freezing significantly at high doses (10, 30 and 100 mg/kg), while showing no significant effect at low doses (1 and 3 mg/kg). Co-administration of WAY 100,635 (0.15 mg/kg) with citalopram (3 mg/kg) reduced freezing markedly and significantly, as compared with either drug alone. However, the addition of GR 127,935 (4 mg/kg) did not potentiate the effects of citalopram (3 mg/kg) on freezing and did not enhance the effect of WAY 100,635 (0.15 mg/kg) with citalopram (3 mg/kg). Co-administration of WAY 100,635 (0.15 mg/kg) or GR 127,935 (4 mg/kg) gave no effect on high-dose citalopram (30 mg/kg)-induced inhibition of freezing behavior. These results suggest that co-administration of WAY 100,635 (0.15 mg/kg) strengthens the anxiolytic effect of citalopram (3 mg/kg) by facilitating central 5-HT neurotransmission. Since GR 127,935 (4 mg/kg) failed to accelerate the inhibition of freezing induced by citalopram (3 mg/kg) with WAY 100,635 (0.15 mg/kg) or citalopram (3 mg/kg) alone, it is suggested that blocking 5-HT 1A receptors is more effective in facilitating the anxiolytic effect of citalopram than blocking 5-HT 1B/1D receptors.

Inhibitory Effects of Ramosetron, a Potent and Selective 5-HT3–Receptor Antagonist, on Conditioned Fear Stress–Induced Abnormal Defecation and Normal Defecation in Rats: Comparative Studies With Antidiarrheal and Spasmolytic Agents

We examined the effect of ramosetron, a potent serotonin (5-HT)3-receptor antagonist for irritable bowel syndrome with diarrhea, on conditioned fear stress (CFS)-induced defecation and normal (non-stressed) defecation in rats and compared ramosetron with the antidiarrheal agent loperamide and the spasmolytic agents trimebutine and tiquizium. Ramosetron, loperamide, trimebutine, and tiquizium significantly inhibited CFS-induced defecation in a dose-dependent manner with ED50(95% confidence limit) values of 0.019 (0.01 –0.028), 9.4 (4.0 –22), 850 (520 –2,400), and 300 (190 –450) mg/kg, respectively. A significant effect of ramosetron on CFS-induced defecation appeared at 10 min after dosing and was sustained for 8 h. In contrast, loperamide, trimebutine, and tiquizium significantly inhibited CFS-induced defecation between 1 –8, 1 –4, and 1–8h after administration, respectively. High doses of ramosetron did not affect normal defecation, whereas loperamide, trimebutine, and tiquizium significantly inhibited this process. In conclusion, ramosetron has potent, rapid-onset, and long-lasting inhibitory effects on CFS-induced defecation in rats, but does not influence normal defecation. The present findings indicate that ramosetron will be a useful therapeutic agent for irritable bowel syndrome with diarrhea, showing greater efficacy and safety than other antidiarrheal and spasmolytic agents.

Fluoxetine protects hippocampal plasticity during conditioned fear stress and prevents fear learning potentiation

Contextual fear conditioning can produce both changes in hippocampal synaptic efficacy and potentiation of subsequent fear learning. In this study, we tested whether fluoxetine reverses these effects. In the first experiment, we examined alterations of baseline synaptic efficacy and induction of synaptic plasticity in the CA3 region of the hippocampus during re-exposure of rats, treated with fluoxetine (7 mg/kg) or vehicle, in a context where they previously received 15 eyelid shocks or no shock (controls). In the second experiment, fear learning potentiation was examined in rats that were initially submitted to conditioning (15 eyelid shocks) and extinction training and then re-exposed to a less intense stressor (three eyelid shocks). Conditioned fear stress decreased synaptic efficacy and blocked the induction of synaptic potentiation in the fimbria-CA3 pathway. Conditioned rats treated with fluoxetine were protected against these electrophysiological changes and did not differ from controls (i.e., no depression and normal induction of potentiation of synaptic efficacy). However, fluoxetine treatment did not suppress conditioned freezing. After fear extinction, exposure of rats to a subconditioning stressor provoked conditioning (fear learning potentiation) in rats treated with vehicle but not in those treated with fluoxetine. These findings indicate that fluoxetine treatment, which is ineffective on conditioned fear stress-induced freezing, may have beneficial effects on conditioned fear stress-induced disturbance of hippocampal plasticity. These data also suggest that restoration of hippocampal functioning may contribute to protection against exaggerated reactions to mild stressors reported in patients with post-traumatic stress disorder.

Early postnatal stress affects the serotonergic function in the median raphe nuclei of adult rats

Recent studies have focused on the serotonergic mechanism mediated via serotonin (5-HT) receptors underlying regulation of emotional stress during the developmental period. The present study was undertaken to elucidate whether early postnatal stress affects rat brain development and influences the serotonergic function in the midbrain median raphe nuclei (MRN) and dorsal raphe nuclei (DRN) in the adult, focusing on the response to unconditioned fear stress. Rats received aversive foot shock (FS) stimuli at the third week of the postnatal period (3wFS), but not those at the second week (2wFS), had increased percentage of time spent on open arms, estimated by the elevated plus maze test, at the postadolescent period (10–12 weeks old). The anxiolytic behavior observed in 3wFS was similar to that in rats having electrolytic lesion of the MRN, but not the DRN. In addition, the number of MRN 5-HT-immunoreactive cells in 3wFS remarkably was reduced compared to the non-FS control and 2wFS groups. These data suggest that aversive stress at the third week is attributable to the serotonergic function in the MRN underlying regulation of unconditioned fear stress. In other words, the “critical period” appears to be the time of neural circuit development of the MRN serotonergic system, which may be implicated in lifelong susceptibility to emotional stress.

Synergistic effects of tandospirone and selective serotonin reuptake inhibitors on the contextual conditioned fear stress response in rats

The purpose of this study was to investigate the effects of co-administration of tandospirone (a 5-HT 1A receptor agonist) and individual selective serotonin reuptake inhibitors (SSRIs) on the contextual conditioned fear stress, using an anxiety model in rats. One day after fear conditioning, tandospirone (0.3–3 mg/kg, s.c.), paroxetine (5–20 mg/kg, i.p.), fluvoxamine (30–60 mg/kg, i.p.) and citalopram (3–30 mg/kg, i.p.) significantly inhibited the conditioned freezing in a dose-dependent manner, whereas, 14 days after fear conditioning, the anxiolytic effects of these drugs were weakened. Fourteen days after fear conditioning, co-administration of tandospirone (0.3 mg/kg, s.c.) with each SSRI [paroxetine (5 mg/kg, i.p.), fluvoxamine (30 mg/kg, i.p.) and citalopram (10 mg/kg, i.p.)], given at subeffective doses, markedly inhibited the conditioned freezing without affecting the locomotor activities and CYP3A4-related pharmacokinetic drug–drug interaction. These results elucidate the pharmacodynamic synergistic effects of tandospirone and SSRIs. Therefore, this augmentation therapy (SSRI + 5-HT 1A receptor agonist) may prove useful for some anxiety disorders.

Effects of cytochrome P450 (CYP) 3A4 inhibitors on the anxiolytic action of tandospirone in rat contextual conditioned fear

The azapirone derivatives, including tandospirone and buspirone, are anxiolytics with 5-HT 1A receptor agonistic action. Previous in vitro studies have suggested these azapirone derivatives are mainly metabolized by the cytochrome P450 (CYP) 3A4 isoform. The purpose of this study was to clarify the effects CYP3A4 inhibitors have on the anxiolytic action of tandospirone in a conditioned fear stress rat model. One day after fear conditioning, the orally administered tandospirone (30–100 mg/kg) significantly inhibited conditioned freezing in a dose-dependent manner. Co-administration of oral tandospirone and CYP3A4 inhibitors [ketoconazole (10 mg/kg, i.p.) and cimetidine (200 mg/kg, p.o.)] markedly inhibited conditioned freezing. Ketoconazole significantly increased the anxiolytic effect of buspirone similar to tandospirone. As with freezing behavior, the plasma concentrations of tandospirone and buspirone were increased by CYP3A4 inhibitors. This suggests the CYP3A4 isoform is involved in the metabolism of tandospirone, in vivo. Therefore, drugs with CYP3A4 inhibitory property may facilitate the anxiolytic effect of tandospirone when treating human anxiety disorders.

An mGluR2/3 antagonist, MGS0039, exerts antidepressant and anxiolytic effects in behavioral models in rats

Abnormalities of glutamatergic neurotransmission have been reportedly observed in psychiatric disorders. Previously, we demonstrated that (1R, 2R, 3R, 5R, 6R)-2-Amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039) is a selective antagonist for group II metabotropic glutamate receptors (mGluR2/3), and that it exerted antidepressant effects in some animal behavioral tests. In the present study, we provide additional evidence that MGS0039 exhibits antidepressant and anxiolytic effects in experimental rodent models, which are predictive of clinical efficacy. The learned helplessness (LH) paradigm, which is a common model used to examine the depressive state, was used to assess antidepressant effects of MGS0039. Moreover, anxiolytic effects of MGS0039 were investigated in the conditioned fear stress (CFS) model, which represents emotional abnormality, including anxiety. Intraperitoneal administration of MGS0039 (10 mg/kg) to rats for 7 days elicited a significant reduction in escape failures in the LH paradigm. In addition, rats treated with MGS0039 (2 mg/kg) showed significantly attenuated freezing behavior in a CFS model, indicating the anxiolytic-like potential of MGS0039. These results suggest that the blockade of mGluR2/3 with MGS0039 may be effective in the treatment of depressive and anxiety disorders.

Target brain sites of the anxiolytic effect of citalopram, a selective serotonin reuptake inhibitor

The purpose of the present study was to elucidate the brain regions in which citalopram, a selective serotonin reuptake inhibitor (SSRI), exerts its anxiolytic effects in conditioned fear stress (CFS) in rats, an animal model of anxiety. The effect of citalopram on CFS-induced c-Fos expression was investigated using immunohistochemistry. Systemic administration of citalopram attenuated contextual CFS-induced c-Fos expression in the secondary motor cortex, primary somatosensory cortex, and basolateral nucleus of the amygdala. Among these regions the basolateral nucleus of the amygdala is a likely candidate region in which citalopram exerts its anxiolytic effect.

5-HT 1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT 1A receptors in the hippocampus and amygdala

Evidence from preclinical and clinical studies has shown that 5-HT 1A receptor agonists have anxiolytic actions. The anxiolytic actions of 5-HT 1A receptor agonists have been tested by our previous studies using fear conditioning. However, little is known about the brain regions of anxiolytic actions of 5-HT 1A receptor agonists in this paradigm. In the present study, we investigated the effects of bilateral microinjections of flesinoxan, a selective 5-HT 1A receptor agonist, into the hippocampus, amygdala and medial prefrontal cortex on the expression of contextual conditioned freezing and the defecation induced by conditioned fear stress in rats. These results reveal that both intrahippocampal and intraamygdala injections of flesinoxan decreased the expression of conditioned freezing, while injections into the medial prefrontal cortex did not. In addition, intraamygdala injection of flesinoxan attenuated the increased defecation induced by conditioned fear, but injections into the hippocampus and medial prefrontal cortex failed. These results suggest that flesinoxan exerts its anxiolytic actions in the fear conditioning through stimulations of the postsynaptic 5-HT 1A receptors in the hippocampus and amygdala.

Lesions of the habenula produce stress- and dopamine-dependent alterations in prepulse inhibition and locomotion

The habenula complex modulates the activity of dopamine and serotonin systems in the brain. An important question remains whether there is a link between habenula dysfunction and monoamine-related disorders, such as schizophrenia. In this study, we describe an interaction between habenula lesions and stress that produces long-lasting effects on behavior. Mice received control lesions or bilateral electrolytic lesions of the habenula and were tested for fear-potentiated startle and freezing measures of conditioned fear. They were also tested for prepulse inhibition (PPI) and locomotor activity in the presence or absence of a dopaminergic agonist (apomorphine) or an atypical antipsychotic with mixed dopamine/serotonin antagonist properties (clozapine). There were no detectable effects of habenula lesions on fear conditioning and no effects on PPI in the absence of stress. However, following conditioned fear stress, habenula-lesioned animals showed decreased PPI which normalized with clozapine. Lesioned animals also showed diminished activity at baseline, with hyperlocomotion following apomorphine. These data support the hypothesis that the habenula may be normally involved in stress-dependent regulation of monoamine systems.

The pharmacokinetics and pharmacodynamics of tandospirone in rats exposed to conditioned fear stress

The 5-HT1, agonist tandospirone is generally thought to have a weak anxiolytic effect with a slow onset of action. Our recent clinical study suggested that a comparatively high dose of tandospirone has excellent anxiolytic efficacy and is without significant adverse effects. The present study was designed to clarify the relationship between the anxiolytic effect of tandospirone and its plasma and brain concentrations. The anxiolytic effect was estimated by determining the conditioned fear stress-induced freezing behavior in rats after tandospirone administration. Obvious correlations between anxiolytic effect and brain concentration of tandospirone were observed 0.5 and 4 h after tandospirone administration, while the anxiolytic effect was dependent on the plasma concentration of at 0.5 h but not 4 h after tandospirone administration. The plasma concentration was significantly correlated with the brain concentration. These findings suggest that the potency of the anxiolytic effect is dependent on both the plasma and brain concentration.

Amygdalic levels of dopamine and serotonin rise upon exposure to conditioned fear stress without elevation of glutamate

Conditioned fear is an artificial stress, induced by a stimulus, such as a tone, that does not elicit fear in nature. This fear response is acquired by experimental animals when tone is combined with an unconditioned stimulus, such as electrical foot shock. The amygdala is considered to be the area involved in acquisition, consolidation and recall of fear. A series of previous pharmacological studies showed antagonists of dopamine D 1 and D 2, glutamate N-methyl- d-asparatate and (±)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors to prevent the acquisition of conditioned fear. However, little is known about the types of neurotransmitters released when conditioned fear is acquired and recalled. The present study was designed to continuously monitor changes in extracellular levels of glutamate, dopamine and serotonin in the amygdala, at the acquisition of conditioned fear on Day 1 and at fear recall in response to a tone as a conditioned stimulus on Day 2, using the in vivo microdialysis method. Glutamate was elevated only on Day 1, while dopamine and serotonin rose on both days. The periods of elevated dopamine and serotonin were longer on Day 1 than on Day 2. These results suggest that greater amounts of glutamate, dopamine and serotonin are necessary for acquisition than for recall of conditioned fear.

Chronic treatment with milnacipran reverses the impairment of synaptic plasticity induced by conditioned fear stress

Recent studies have focused on neural plasticity at the cellular and molecular levels in the etiology and treatment of stress-related disorders; however, there are no reports concerning modulation of synaptic plasticity in the hippocampus underlying therapeutic effects of antidepressants and/or anxiolytics. To elucidate the functional interaction between the stress-induced alteration of synaptic plasticity and therapeutic effects, we examined the anxiolytic mechanism(s) of milnacipran, focusing on modulation of long-term potentiation (LTP) in the hippocampal CA1 field. Rats that received footshock stimulation five times (intensity, 0.5 mA; duration, 2 s; shock interval, 30 s) for 5 days were treated with milnacipran (30 mg kg(-1), p.o.) or vehicle for 14 days. On the 15th day, rats were subjected to conditioned fear stress (CFS) to evaluate freezing behavior. Separate from the behavioral study, electrophysiological approach was performed to evaluate the synaptic efficacy under anesthesia. Exposure to CFS suppressed LTP in the CA1 field. Chronic treatment with milnacipran (30 mg kg(-1), i.p. after 30 mg kg(-1) day(-1), p.o. x14 days), but not acute treatment (30 mg kg(-1), i.p. after vehicle 5 ml kg(-1) day(-1), p.o. x14 days), reduced freezing behavior and reversed the impairment of LTP induced by CFS. The present data suggest that a correspondence exists between fear-related behavior and synaptic plasticity in the hippocampus. In other words, anxiolytic mechanism(s) of chronic treatment with milnacipran may be explained by reversal effects on the psychological stress-induced impairment of synaptic plasticity.

An Investigation Into The Quality Of Service Delivered By The South African Police Service In The North Rand, Gauteng

An investigation was conducted into the level and quality of service delivered by the SAPS in the Client Service Centres (CSC). Quality was measured in terms of the principles of batho pele. The concept of ubuntu was introduced to see how it could be used to enhance these principles. A customer service model was developed and used to evaluate the quality of service rendered. Interviews were conducted with staff, customers and managers. The results of the study showed that employees of the SAPS do not experience internal quality. The customers also do not receive service of a good quality as the principles of batho pele were not applied. 
 
 Opsomming’n Ondersoek is geloots, met betrekking tot die kwaliteitsvlakke van diens lewering by die Suid Afrikaanse Polisiediens se Kliente Diens Sentrums. Die kwaliteit van diens lewering word gemeet aan die maastawwe van die batho pele beginsels. ’n Kliente diens model is vir hierdie doel ontwerp om die kwaliteit van dienste gelewer te bepaal. Die resultate van hierdie studie toon dat die werknemers van die SAPD ondervind nie interne kwaliteit nie en hul nie die beginsels van batho pele implementeer nie.

Characterization of the anxiolytic-like effects of fluvoxamine, milnacipran and risperidone in mice using the conditioned fear stress paradigm

It has been known that rodents exhibit the immobility when tested in the same environment in which they had been previously exposed to aversive stimuli. This behavior is called conditioned fear stress-induced freezing behavior, and has been used as a model of anxiety. Using this animal model, the present study tried to characterize the anxiolytic-like effects of fluvoxamine, a selective serotonin reuptake inhibitor, milnacipran, a serotonin noradrenaline reuptake inhibitor and risperidone, an atypical antipsychotic in mice. Fluvoxamine (1.25–10 mg/kg, intraperitoneally (i.p.)) and milnacipran (0.5–4 mg/kg, i.p.) each dose-dependently and significantly suppressed the conditioned fear stress-induced freezing behavior in mice, an indicator of anxiety, and milnacipran had a weaker effect than fluvoxamine. While risperidone also significantly suppressed freezing behavior at a low dose (0.01 mg/kg, i.p.), a high dose (0.04 mg/kg, i.p.) decreased spontaneous motor activity. On the contrary, sulpiride, a typical antipsychotic (2–8 mg/kg, i.p.), did not affect freezing behavior. In a combination study, the suppressive effect of a low dose of risperidone (0.01 mg/kg, i.p.) on freezing behavior was significantly antagonized by the co-administration of low/middle doses of fluvoxamine (1.25 and 2.5 mg/kg, i.p.), whereas a high dose of fluvoxamine (10 mg/kg, i.p.) was unaffected. Additionally, the co-administration of milnacipran (0.5–2 mg/kg, i.p.) also tended to inhibit the suppressive effect of risperidone (0.01 mg/kg, i.p.). These findings indicate that fluvoxamine, milnacipran and risperidone may each be clinically effective at treating anxiety disorders, but their effects may be attenuated in combination with other medications.

Escitalopram: a unique mechanism of action

The 5-HT (5-hydroxytryptamine, serotonin) transporter (SERT) mediates the reuptake of 5-HT from the synaptic cleft into the neuron, and inhibition of this uptake is the target of selective serotonin reuptake inhibitors (SSRIs). Escitalopram (S-citalopram) is the most selective SSRI available, whereas the other enantiomer, R-citalopram, is approximately 30–40 times less potent than the S-enantiomer. Both biochemical experiments (measurement of extracellular 5-HT in the frontal cortex of rats) and behavioural studies (using the chronic mild stress and conditioned fear stress models) demonstrate that R-citalopram appears to counteract the effect of escitalopram, and that it is a dose-dependent action. When escitalopram is administered at a specific dose, it produces a greater effect than when the same dose of the S-enantiomer is administered in combination with the R-enantiomer, i.e. when citalopram is administered. While mainly the S-enantiomer is bound to the primary binding site on the SERT, both enantiomers bind to the allosteric binding site. However, the R-enantiomer stabilises the binding of the S-enantiomer at the primary site less than the S-enantiomer. Furthermore, R-citalopram has an inhibitory effect on the association of escitalopram with the transporter, thereby possibly reducing escitalopram's effect. In summary, escitalopram appears to possess a unique mechanism of action at the 5-HT transporter protein. Furthermore, escitalopram (S-citalopram) is different from citalopram because R-citalopram counteracts the activity of the S-enantiomer.